RS20110079A - Microbiological procedure for obtaining 7alpha-substituted 11alpha-hydroxysteroids - Google Patents

Abstract

Invention herewith described refers to a new way of synthesis for obtaining initial products for getting compounds of the general formula (8,10,and 12). This synthesis results in microbial reaction compounds of the general formula (4, B). Meanings of the residuals R7, R10, R11, R13, R17 and R17' and groups U-V-W-X-Y-Z are listed in the patent claims.

Description

Microbiological procedure for obtaining 7<x-substituted 11a-hydroxysteroids

Description:

The invention relates to the process for obtaining 7a-substituted 11a-Hydroxysteroids, 7a,17a-substituted lip-halogensteroids that can be obtained from them, the process for obtaining the latter compounds as well as their application and pharmaceutical preparations containing these compounds. In addition, the invention relates to further 7a-substituted 11<p>~halogensteroids, namely 7a-substituted Estra-1,3,5-(10)-trienes, which can be obtained from 7a-substituted 11a-Hydroxysteroids.

For the treatment of Climacterium virile and for the development of male sexual organs as

Androgens, especially testosterone, are used for male fertility control. These hormones also have partially anabolic active components that, among other things, promote muscle growth.

Virile climacteric is characterized by age-related delay in the body's own production of androgens, so hormone replacement therapy (HRT: hormone replacement therapy) is used for treatment.

LH-RH administration for male fertility control leads, in addition to reduced spermatogenesis, to the secretion of LH and to a decrease in testosterone levels.

and libido, which is equalized by giving testosterone drugs (D. E. Cummings et al., "Prostate Sparing Effects of the Potent Androgen 7a-Methyl-19-Nortestosterone: A Potential Alternative to Testosterone for Androgen Replacement and Male Contraception", Journal of Clinical Endocrinology and Metabolism, Vol. 83, Nr. 12 pages 4212-4219

(1998)).

Combination therapy by administration of androgens and some gestagen-acting component can be used to control male fertility (see for example WO 01/60376 A and the documents cited therein).

During treatment with testosterone, it has been shown that side effects appear, especially the enlargement of the prostate due to the numerical increase of stromal cells and glands (BPH: benign prostatic hyperplasia). 5a-reductase-mediated metabolism of testosterone produces dihydrotestosterone (DHT), which, among other things, can lead to the development of BPH (Cummings et al., ibid.; WO99/13883 Al). 5a-Reductase inhibition is therefore used in the clinic to treat BPH (Finasteride)

The rapid metabolism of the androgenic steroid testosterone in the human body leads not only to the creation of unwanted DHT, but also to the need for oral administration of a higher dose to reach the level of testosterone action. Therefore, alternative forms of giving are needed, such as m.-injections or large patches.

As a replacement for testosterone in the mentioned areas of indications, 7a-Methyl-19-nortestosterone (MeNT) has been proposed, which on the one hand has a higher biological activity than testosterone, since it has a higher binding affinity to androgen receptors. On the other hand, probably due to the steric hindrance of the 7α-Methyl group, it resists metabolism by 5α-reductase (Cummings et al., ibid., WO 99/13883 A1, WO 99/13812 A1, US-A-5,342,834).

During the metabolism of testosterone, a smaller part of this compound is further converted into estradiol by aromatizing the ring A of the steroid system, especially in the brain, liver and fat tissue. Considering the overall effect of testosterone and its metabolites, estradiol is responsible for sex-specific behavior and is responsible for gonadotropin-regulation. Therefore, its effect, just like that of testosterone, can be considered favorable for an adult man. (Cummings et al., ibid.).

However, it turned out that the pharmacokinetics of testosterone is not satisfactory. Testosterone in particular is quickly excreted again when administered orally, so the effectiveness and duration of action of drugs made from it are unsatisfactory. This is why other testosterone derivatives have been synthesized. Derivatives of this type are described inter alia in US-A-5,952,319, in particular 7a-, 11 p-Dimethylderivatives of 19-Nortestosterone, namely 7a, 11 P-Dimethyl-17p-hydroxy-4-en-3-one, 7a, 11 P-Dimethyl-17P-heptanoyl-xyestr-4-en-3-one, 7a, 11 P-Dimethyl-17P-[[2-cyclopentylethyl)carbonyl]-estr-4-en-3-one, 7a,l lp-Dimethyl-17p-(phenylacetyloxy)-estr-4-en-3-one and 7a,1 ip-Dimethyl-17P-[[(trans-4-[«-butyl]cyclohexyl)-carbonyl]-oxy]-estr-4-en-3-one.

The mentioned 7a, 11 p-Dimethylderivatives possess as MeNT the previously mentioned advantages, including improved pharmacokinetics, which means their efficiency and duration of action are improved compared to testosterone. However, these derivatives can only be produced through complicated methods of synthesis.

Microbiological synthesis of steroids is described in EP 0 900 283 BI. It is stated there that Estr-4-ene-3,17-dione and Canrenone can be transformed into the corresponding lla-Hydroxy analog with the application of some microorganisms, selected from the group, which includes Aspergillus nigricans, Rhizopus arrhizusi strains of Pestelotia. However, the introduction to the description also refers to Schibahara et al., Biochem. Biophys. Acta (1970), 172-179, who reported that the microbiological reaction of 1 la -hydroxylation on steroids is unpredictable.

Since then, the proposed invention has been based on a problem, the invention of testosterone derivatives, which are not sensitive to reduction by 5α-reductase, which also have improved pharmacokinetics and which, in particular, can be easily produced. A very important aspect of the proposed invention therefore consists in finding a method for better access to the preceding stages, so that the preceding stages are easier to obtain.

The problem underlying the proposed invention is solved by a microbiological process for obtaining 7a-substituted steroids according to claims 1, 3 and 6, 7a, 17a-substituted 11 P-halogensteroids according to claim 11, a process for obtaining 7a, 17a-substituted lip-halogensteroids according to claims 23, 24 and 25, application of these 7a, 17a-substituted 11 p-halogensteroids according to claim 26, pharmaceutical preparations containing these 7a, 17a-substituted 11 p-halogensteroids according to claim 27 as well as 7a, substituted 1 ip-Halogenestra-1,3,5(10)-triene according to claim 21. Favored forms of the claimed articles are listed in the subclaims.

Definitions:

The following definitions apply to all parts of the description and claims as well as to the attached scheme I: All groupings, residues or other structural units can each independently of each other be varied within the indicated areas of meaning.

All alkyl-, alkylene-, alkenyl-, alkenylene-, alkynyl-, alkynylene-groups can be either straight chain or branched. For example, a propenyl group can be described by one of the following chemical structures: -CH=C-CH3, -CH2-C=CH2, -C(CH3)=CH2. Thus, under Cr to C18-alkyl fall, for example, methyl, ethyl, w-propyl, i-propyl, "-butyl, z-butyl, "-pentyl, z-pentyl, r-pentyl, rc-pentyl, 77-hexyl, 1-Methyl-n-pentyl, 2-Methyl-"-pentyl, 3-Methyl-"-pentyl, 4-Methyl-n-pentyl, 1-Ethyl-"-butyl, 2-Ethyl-«-butyl and so on.

Alicyclic alkyl is either cycloalkyl or cycloalkyl substituted with one alkyl group or with several alkyl groups, which are directly attached via the cycloalkyl ring or via one alkyl group.

In the same way, alicyclic alkenyl or cycloalkenyl or one with one or more alkenyl groups or one or more alkenyl- and alkyl groups or one or more alkyl groups substituted cycloalkenyl or cycloalkyl, which is directly linked via a cycloalkenyl ring or via one alkenyl- or in a given case alkyl group, whereby at least one double bond is contained in alicyclic alkenyl.

Aryl can first be phenyl, but also 1-Naphthyl, 2-Naphthyl. Aryl includes in principle also heteroaryl, especially 2-,3- and 4-pyridinyl, 2- and 3-furyl-, 2- and 3-thienyl-, 2- and 3-pyrrolyl-, 2-,4- and 5-imidazolyl-, pyridazinyl, 2-,4- and 5-pyrimidinyl as well as 3- and 4-pyridazinyl.

Halogen is fluorine, chlorine bromine or iodine.

Pharmaceutically acceptable addition salts are salts of the corresponding compounds with inorganic or organic acids, for example with hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, citric acid, oxalic acid, tartaric acid and methanesulfonic acid. Esters can be built especially with succinic acid.

Superimposed numbers on the symbols, for example R , indicate their position on the steroid skeleton, where C-atoms in the steroid skeleton are numbered according to the IUPAC nomenclature. The superimposed numbers on the C symbols, for example C<10>, indicate the position of the corresponding carbon atom in the steroid ring.

Description of the invention:

New microbiological procedures serve to obtain 7a-substituted 11a-hydroxysteroids of the general formula 4,B:

in which

R<7>grouping P-Q,<p>why

P represents Ci- to C4-alkylene and Q is hydrogen, Cr to C4-alkyl or Cido C4-fluoroalkyl (alkyl partially or fully fluorinated) and the P-Q group is linked to the steroid skeleton through P,

R<10>is H, CH3 or CF3i

R13 is methyl or ethyl.

In one of the first variants of the process for obtaining these substances, a suitable 7a-substituted steroid of the general formula 3,A is hydroxylated and oxidized in one step of the process:

in which R7, R1<0>and R<13>i<m>have the same meaning as stated for the compounds of the general formula 4,B, with the use of a microorganism selected from the group comprising Aspergillus sp., Beauveria sp., Glomerella sp., Gnomonia sp., Haplosporella sp. and Rhizopus sp. are particularly suitable

Apergillus Awamori, Aspergillus fischeri, Aspergillus malignus, Aspergillus

niger, Beauveria bassiana, Glomerella cingulata, Gnomonia cingulata,

Haplosporella hesperedica and Rhizopus stolonifer, where Apergillus Awamori (CBS), Aspergilus fischeri (ATCC 9142), Aspergilus malignus (IMI 16061), Aspergilus niger (ATCC 9142), Beauveria bassiana (ATCC 7159), Glomerella cingulata (CBS 15226, CBS 23849, CBS 98069) are especially used. ATCC 56596, ATCC 64682, IFO 6425, Gnomonia cingulata (CBS 15226), Haplosporella hesperedica (CBS 20837) and Rhizopus stolonifer (ATCC 15441).

This microbiological production process can be performed in two stages, where the hydroxylation and oxidation reactions take place in two subsequent stages, one after the other. During the reaction, the duration of the reaction can be controlled: By stopping the reaction after a certain time, the hydroxylated but not the oxidized species can be isolated. Both stages of the process can therefore be carried out separately or in a single fermenter with a bladder.

A compound of the general formula 3,A can be hydroxylated at the 11-position in a first stage of a microbiological process using a first microorganism selected from the group consisting of Aspergillus

sp., Beauveria sp., Gibberella sp., Glomerella sp., Gnomonia sp.,

Metarrhizium sp., Nigrospora sp., Rhizopus spiVerticillium sp., whereby a 7a-substituted steroid with a hydroxyl group in position 1 la is built. This compound has the general formula C:

in which R<7>, R<10> and R<13>i<m>have the same meaning as previously stated for the compound of general formula 4,B. In particular, Aspergillus malignus is used,

Aspergilus melleus, Aspergilus niger, Aspergilus ochraceus, Beauveria

bassiana, Gibberella fujikuroi, Gibberella zeae, Glomerella cingulata,

Glomerella fusaroides, Gnomonia cingulata, Metarrhizium anisopliae,

Nigrospora sphaerica, Rhizopus stolonifer, Rhizopus oryzaei

Verticillium dahliae. Aspergilus malignus (IMI 16061), Aspergilus melleus (CBS), Aspergilus niger (ATCC 11394), Aspergilus ochraceus (NRRL 405, CBS 13252, ATCC 46504), Beauveria bassiana (ATCC 7159, IFO 5838, ATCC 13144, IFO 4848, CBS 11025, CBS 12736), Gibberella fujikuroi (ATCC 14842), Gibberella zeae ( CBS 4474), Glomerella cingulata (ATCC 10534, CBS 23849, CBS 23749, ATCC 16646, ATCC 16052, IFO 6459, IFO 6425, IFO 6470, IFO 5257. oryzae (ATCC 4858, ATCC 34102, ATCC 34102) and Verticillium dahliae (ATCC 11405).

The intermediate product C is then oxidized in the next step of the microbiological process with the use of another microorganism selected from the group consisting of Bacillus sp., Mycobacterium sp., Nocardia spiPseudomonas to form a 7a-substituted 1 la-hydroxysteroid of the general formula 4,B. Bacillus lactimorbus, Bacillus sphaericus,

Mycobacterium neoaurum, Mycobacterium smegmatis, Nocardia

corallina Nocardia globerula, Nocardia minima, Nocardia restrictus,

Nocardia rubropertincta, Nokarnia salmonicolor and Pseudomonas

testosterones, in which Bacillus lactimorbus (ATCC245), Bacillus sphaericus (ATCC 7055), Mycobacterium neoaurum (ATCC 9626, NRRL B-3683, NRRL B-3805), Mycobacterium smegmatis (ATCC 14468), Nocardia corallina (ATCC 31338), Nocardia globerula (ATCC 9356), Nocardia minima (ATCC 19150), Nocardia restrictus (NCIB 10027), Nocardia rubropertincta (ATCC 14352), Nokarnia salmonicolor (ATCC 19149) and Pseudomonas testosteroni (ATCC 11996).

In a further variant of the procedure, compounds of the general formula 4,B can be obtained in a microbiological reaction from 7a-substituted steroids of the general formula D:

in which R<7>, R<10> and R<13>i<m> have the same meanings as stated for the compounds of the general formula 4,B. This reaction is carried out using a

microorganism, selected from the group, which includes Aspergillus sp.,

Beauveria sp., Curvularia sp., Giberella sp., Glomerella sp., Gnomonia

sp., haplosporella sp., Helicostyllum sp., Nigrospora sp., Rhizopus sp., and

Syncephalastrum sp., in which the steroid skeleton is hydroxylated in the 11a position, resulting in a 7a-substituted 11a-hydroxysteroid of the general formula 4,B. Aspergilus alliaceus, Aspergilus are primarily used

awamori, Aspergilus fischerei, Aspergilus malignus, Aspergillus melleus,

Aspergillus nidualans, Aspergillus niger, Aspergillus ochraceus,

Aspergilus variecolor, Beauveria bassiana, curvularia lunata, Gibberella

zeae, Glomerella cingulata, Glomerella fusaroides, Gnomonia cingulata,

Haplosporella hesperedica, Helicostylum piriformea, Nigrospora

sphaerica, Rhizopus oryzaeiSyncephalastrum racemosum, especially Aspergilus alliaceus (ATCC 10060), Aspergilus awamori (CBS), Aspergilus fischerei (ATCC 1020), Aspergilus malignus (IMI 16061), Aspergillus melleus (CBS), Aspergillus nidualans (ATCC 11267), Aspergilus niger (ATCC 9142, ATCC 11394); lunata (1X3), Gibberella zeae (CBS 4474), Glomerella cingulata (ATCC 10534, CBS 23849, CBS 23749, ATCC 16646, IFO 6459, IFO 6425, IFO 6470, ATCC 15093, ATCC 10529, IFO 5257, ATCC 56596, ATCC 64682), Glomerella fusaroides (ATCC 9552), Gnomonia cingulata (CBS15226), Haplosporella hesperedica (CBS 20837), Helicostylum piriformea (ATCC 8992), Nigrospora sphaerica (ATCC 12772), Rhizopus oryzae (ATCC 4858) and Syncephalastrum racemosum (IFO 4827).

Particularly suitable processes are those which obtain 7a-substituted 11a-hydroxysteroids of the general formula 4,B, in which independently R<7>represents CH3 and/or R<10>represents H and/or R<13>represents CH3.

The procedure is carried out in the usual way. For this, a sterilized nutrient medium for the strain is typically produced first, and this nutrient solution is inoculated with the soybean culture solution, in order to grow the strain. The pre-culture produced in this way is then transferred to the fermenter, which is also charged with a suitable nutrient solution. It is convenient, after the growth phase of the strain culture, to add the starting substance to the fermenter, in the proposed case it means either one compound of the general formula 3, A or one compound of the general formula D, so that the reaction according to the invention can take place. After completion of the reaction, the mixture is processed in the usual way to isolate the desired 7α-substituted 1α-hydroxysteroid.

From the thus obtained compounds of the general formula 4,B, further compounds according to the invention can be synthesized with also methods according to the invention. Especially the 7a,17a-substituted lip-halosteroids of the general formula 8,10,12 represent valuable active components:

U-V-W-X-Y-Z stands for one of the ring structures C'-C2-CJ-C<4>=C<5->C'°, Cl- C2- C2- CA- C5=Cw or C'-C<2->C<3->C<4->C5-C<10>, in which case one oxygroup (=0) is attached to W (=C), or to the ring structure C1=C2-C3=C4-C5=C6, where in this case the OR residue is bound to W (=C?)

R<3> stands for H, C1- to C4-alkyl, C1- to C4-alkanoyl, or one cyclic C3- to C7-ether with an O atom of the OR<3->residue

R7 is the grouping P-Q, where it represents

P is a Cr to C4-alkylene and Q is a hydrogen, Cr to C4-alkyl or Cr to C4-fluoroalkyl

and the P-Q group is attached via P to the steroid skeleton

R<10>can be a- or B-positional and radiate to H, CH3 or CF3i

? only then is it present. When X-Y-Z is not; C4-C5=C10 R<n>ehalogen

R13 is methyl or ethyl

R<17> is also with H, C1- to C18-alkyl, alicyclic Q- to C18-alkyl, Cr to C18-alkenyl, alicyclic C10-C18-alkenyl, Cr to C10-alkynyl, Cr to C10-alkylaryl, Cr to C8-alkylene nitrile or for the group P-Q, wherein the group P-Q has the aforementioned meaning R st<o>i for H, Ci-do C18-alkyl, alicyclic C1-to C18-alkyl, d-to C18-alkenyl, alicyclic Cr to C18-alkenyl, C10-C18-alkynyl or C10-C18-alkylaryl, wherein R<17>' can also be attached via a keto group to the 17B-oxy group, and wherein R17' can additionally be substituted with one or more groups NR<18>R<19> or with one or more group SOxR<20>, where x<=>0, 1 or 2 and R18, R<19> and R<20> always independent of each other, can have the same meaning as R<17>

ao and their pharmaceutically acceptable addition salts, esters and amides. These compounds, which can be obtained by further steps of the procedure from 7a-substituted 11a-hydroxysteroids of the general formula 4,B, are valuable

active substances with a strong androgenic effect without the mentioned side effects. These compounds are suitable for obtaining drugs, especially effective contraceptives and active substances for hormone replacement therapy (HRT).

In case R 17' is additionally substituted with the group NR 18 R 19, it can be a methylamino-, dimethylamino-, ethylamino-, diethylamino-, cyclohexylamino-, dicyclohexylamino-, phenylamino-, diphenylamino-, benzylamino- or dibenzylamino group.

Particularly favorable 7a,17a-substituted 11 P-halogensteroids of the general formula 8,10,12 are compounds in which U-V-W-X-Y-Z stands for the ring structure C'-C^-C^C'-C10, C'-C^-C^C^C10 or C^-C^C<4->C5=C10.

In the first case (U-V-W-X-Y-Z= C<1->C<2->C<3->C<4->C<5>=C<10>) it is a steroid of general formula 10:

In the second case (U-V-W-X-Y-Z= C'-C^-C^-C^C10) it is about steroids of the general formula 12:

The compounds of general formulas 10 and 12 are androgenic compounds.

In the third case (U-V-W-X-Y-Z = C*<:2-C3=C4-C5=C6) we are dealing with steroids of the general formula 8: These compounds are estrogens (affinity compounds of estrogen receptors). In all three cases, the residues R<3>, R<7>, R10, R11, R13, R<17> and R17 have the same meanings as the corresponding residues in the general formulas 8, 10, 12. Primarily, independently of each other, R 1 stands for H, and/or R 7 for CH3 and/or R<11> for fluorine and/or R<13> for CH3 and/or R17 for H, CH3, C 10 C18 alkynyl, especially ethynyl, CH2CN or CF3 and/or R<17>' for H. Particularly advantageous 7a, 17a-substituted 11 p-halosteroids according to the invention general formulas 8,10,12 are: 17a-Ethynyl-l ip-fluoro-17p-hydroxy-7a-methylestr-4-en-3-one (formula 10) 17a-Ethynyl-l 1 P-fluoro-17p-hydroxy-7a-methylestr-5(10)-en-3-one (formula 2) 17a-Ethynyl-l 1 p -Fluoro-7a-methylester-1,3,5(10)-triene-3-17P-diol (Formula 8). To obtain these compounds, it is possible to follow the following methods: To obtain 7a-17a-substituted 11 p-halogensteroids of the general formula 10 in which U-V-W-X-Y-Z stands for the ring structure C<1->C<2->C<3->C<4>=C<5->C<10>, 7a-substituted 1 la-hydroxysteroids of the general formula 4.B are used as starting substances. eni by the microbiological process according to the invention. In the first step of the synthesis, these 7a-substituted 1 la-hydroxysteroids are converted into the corresponding 7a-substituted lip-halogensteroids 5 by nucleophilic substitution with some halodehydroxylating reagent: ;As halodehydroxylating reagents, all common reagents come into consideration, for example hydrofluoric, chloric, bromic, or hydroiodic acid, thionyl chloride or thionyl bromide, phosphorus pentachloride, phosphorus oxychloride, N-chlorosuccinimide, triphenylphosphine/carbon tetrachloride, HF/pyridine or diethylamino-sulfur trifluoride or preferably nonaphylfluoride/1,5-diazabicyclo-[5,4,0]undecene. From 5, compound 10 was obtained by selective alkylation at C 17 of the ring skeleton (see scheme I for this). For selective alkylation, conventional alkylation reagents, for example, Grignard compounds, and organometallic compounds, especially alkyllithium compounds, can be used. For example, to obtain the corresponding 17a-Etmyl-17P-hydroxy-estr-4-en-3-one from Estr-4-en-3,17-dione, ethynylmagnesium bromide can be used as an alkylating reagent. ;To obtain 7a,17a-substituted 11<p->halosteroids, in which U-V-W-X-Y-Z stands for the ring structure C 1 -C 2 -C 3 -C 4 -C 5 =C 10 and having the general formula 12, the general formulas 10 are used, which are isomerized, so that the A<4>-double bond is isomerized into compounds A<5>(<10>)-double bond. In order to protect the 3-keto groups, a cyclic ether is therefore first created in the 3-position. After that, the A<4> double bond is isomerized to the A5(10)-double bond, whereby the 7a, 17a-substituted 11f3-halosteroid of the general formula 12 is built, and the protecting group is cleaved off. To obtain further 7a,17a-substituted 11 p-halosteroids, of the general formula 8 in which U-V-W-X-Y-Z stands for the ring structure C<I=>C<2->C<3=>C<4->C<5=>C<10>, the procedure is as follows: First, as previously described, the corresponding lip-halosteroid of the general formula 5 is created from the microbial hydroxylation and oxidation of the obtained of the 7a-substituted 11a-hydroxysteroid of the general formula 4B and halodehydroxylation by a nucleophilic substitution reaction. From this, oxidation, for example with a copper(II) salt, creates 7a-substituted Estra-1,3,5(10)-triene of the general formula 6: in which R 3 , R 7 , R 11 and R 13 have the same meanings as previously indicated. As long as R<3> stands for H, these compounds can be directly synthesized. If instead of H there is some other residue for R, the corresponding ethers or esters must be made in a known way, since the 1,3,5(10)-triene ring is made by oxidation. ; 7a-substituted 1 and -halogenestra-1,3,5(10)-trienes of the general formula 6 are also new as are their pharmaceutically acceptable addition salts, esters and amides and are therefore protected as by-products in the synthesis, also according to the invention, of 7a, 17a-substituted 11 P-halogensteroids of the general formula 8. ;Especially suitable 7a-substituted 1 ip-halogenestra-1,3,5(10)-triene of general formula 6 is 1 ip-Fluoro-3-hydroxy-7a-methylestra-1,3,5(10)-trien-17-one. From 7a-substituted lip-halogenestra-1,3,5(10)-trienes of formula 6, in the same way as previously described for the synthesis of compounds of general formula 10, by selective alkylation at C17 of the ring skeleton, 7a,17a-substituted 11 P-halogensteroids of general formula 8 can be made. Furthermore, they can be obtained from, by microbial hydroxylation and oxidation 7a-substituted steroids of the general formula 3,A or D, obtained substances of the general formula 4,B also 7a-substituted 11 p-halogen steroids of the general formula 9, which also possess androgenic action: in which R<7>, R11 and R<13>have the same meaning as stated above. A particularly suitable compound is 1 ip -Fluoro-17P-hydroxy-7a-methylestr-4-en-3-one. Compounds of general formula 9 as well as their pharmaceutically acceptable addition salts, esters and amides also show androgenic effects. To obtain compounds of general formula 9, Estr-4-en-3,17-dione 5 is reduced to 17p-Hydroxy-estr-4-en-3-one 9, for example with borohydride. Compounds of general formula 9 can be further translated into the corresponding 7a-substituted 1 ip -halogenestra-5(10)-enes: wherein R<7>, R<10>, R11 and R<13> have the meanings as in general formulas 8,10,12. For this, the compounds of the general formula 9 are isomerized by shifting the A<4>-double bond to the A<5>(,<0>)-double bond. In order to protect the 3-keto group, a cyclic ether at the 3-position is therefore first created. Then, the A-double bond is isomerized to an A<5>(<10>)-double bond, thereby building the aforementioned 7a-substituted 11 P-halogensteroid, and the protecting group is then cleaved off. In conclusion, by isomerizing the A<4->double bond to the A<5>(<10>)-double bond, the corresponding 7a-substituted 1 ip-halogenestra-5(10)-enes can also be obtained from the compounds of general formula 5: where R 7 , R 10 , R 11 and R 13 have the meanings as in general formulas 8,10,12. For this, the compounds of the general formula 5 are isomerized by moving the A<4->double bond into an A<5>(<1>(<?>)-double bond. In order to protect the 3-keto group, a cyclic ether at the 3-position is therefore first created. Then, the A-double bond is isomerized into an A<5>(<10>)-double bond, whereby the aforementioned 7a-substituted lip-halogensteroid, and the protecting group is then cleaved off.

The mentioned compounds can also be further esterified or etherified, as long as there are appropriate hydroxyl groups in position 3 or 17p. For example, compound 9 can be converted to the corresponding 17p-ether or 17p~ ester. A suitable compound is lip-Fluoro-17P-(4-sulfamoylbenzoxy)-7a-methylestr-4-en-3-one. As a substituent on the oxy atom of oxygen on C<17>, basically the same residues that are listed for R<17> come into consideration.

Especially the 7a, 17a-substituted 11P-halosteroids of the general formula 8,10,12 are suitable for the production of drugs. Therefore, the proposed invention also relates to the use of said compounds of the general formula 8,10,12 for the production of drugs and pharmaceutical preparations, which contain at least one of the said compounds of the general formula 8,10,12 as well as at least one pharmaceutically acceptable carrier.

The 7a,17a-substituted 11 p-halogen steroids of the general formula 10,12 are compounds with a strong androgenic effect without the mentioned side effects, for example stimulation of the prostate (especially without benign prostatic hyperplasia). The compounds can be easily synthesized. It has been shown that the compounds according to the invention of the general formula 10 ilil2 can not only be used for male HRT, but also that these compounds, without additional administration of further active substances, are suitable as an effective male contraceptive, if a sufficient dosage is taken, so that the level in the blood of LH, from testosterone produced in the body, as well as FSH (follicle stimulating hormone) is sufficiently lowered. This is because 11 P-halogen steroids inhibit the secretion of LH and FSH. LH stimulates the Lewdig cells so that testosterone is secreted. If the LH level in the blood is kept low, the body's own secretion of testosterone is also lowered. Testosterone is required for spermatogenesis, while FSH stimulates sperm cells. Therefore, for effective spermatogenesis, a sufficiently high FSH and LH level in the blood is required, whereby a sufficiently high LH level in the blood leads to the secretion of testosterone necessary for spermatogenesis.

Since treatment with exclusively 7a,17a-substituted lip-halogen steroids without additional active substances for sterilization can already lead to effective male contraception, the administration of a suitable drug can be simplified and the costs of administration can be significantly reduced.

7a,17a-substituted 11 P-halogen steroids according to the invention can also be used in combination with a progestogen, for the purpose of controlling male fertility.

In addition, the 7a, 17a-substituted 11 P-halosteroids according to the invention effectively inhibit 5a-reductase and steroid-11-hydroxylase [CYP11B

(P450cll), G. Zhang, W. L. Miller, Journal of Clinical Endocrinology and Metabolism, Vol. 81 pages 3254-3256)], so that prostate stimulation is selectively avoided, and these compounds show improved pharmacokinetics. Inhibition of 11-hydroxylase leads to reduced deactivation of androgenic compounds and to their reduced excretion from the human body. Thus, the effectiveness and duration of action of these compounds compared to known compounds, especially after oral application, are improved.

For the above reasons, these compounds are particularly suitable for use in male fertility control as well as androgen replacement therapy with a reduced tendency towards 5a-reduction while maintaining the ability to aromatize into estrogenic steroids and a more favorable effect on serum lipids and the central nervous system.

Androgenic effect and confirmation that the mentioned side effects do not occur was investigated in a seminal vesicle test for the compounds according to the invention of the general formula 10 and 12. The effectiveness of the compound according to the invention of the general formula 8 was tested by the uterine growth test for estrogenic action.

7a, 17a-substituted 11p-halogen steroids according to the invention of the general formula 10 or 12, or pharmaceutical preparations according to the invention, which contain these compounds, are extremely suitable for the treatment of non-sterile male persons as well as primarily male mammals. The use of male contraception results in male individuals becoming sterile only temporarily. After the application of the active components according to the invention, i.e. pharmaceutical preparations, the previous state is re-established, so that the male person is no longer fertile and spermatogenesis takes place in the original way.

scope. In order to keep the state of temporary sterility constant during the desired period of time, the active substance or the preparation should be given continuously, and according to the form of application, the administration should be repeated daily, in shorter or longer time intervals. After the end of a single or repeated administration of the active substance or preparation, the non-sterile state of the male person in the given case is not established immediately, but only slowly, and the time period required for this depends on various factors, for example, on the dosage, the body constitution of the person and the parallel administration of other drugs.

If the purpose of administration is contraception, the dosage of the 7a, 17a-substituted 11 P-halogen steroids must be set so high that the blood level of LH and FSH for each is at most 2.5 IU/ml, especially at most 1.0 IU/ml, and testosterone at most 10 nmol/1, especially at most 3 nmol/1.

If 7a,17a-substituted 11 P-halogen steroids are to be used for HRT, without needing to achieve contraception, the dosage is set lower. In this case, action levels are aimed for, which allow a blood level of LH and FSH of more than 2.5 I.U./ml each and for testosterone of more than 10 nmil/1.

The dosages of the 7a,17a-substituted 11 β-halosteroids according to the invention required to establish the blood levels of LH, FSH and testosterone, of the general formula 10 or 12 depend on a number of factors and must therefore be determined for the specific application. The dosage is first naturally dependent on the type of therapy. In how many compounds should be used for male contraception, significantly higher doses must be given than when used for HRT. Further dosing is also governed by the type of 7a, 17a-substituted lip-halogen steroids and their bioavailability. Furthermore, the type of application is important for the amount that is applied. In the end, the dosage also depends on the physical constitution of the person applying it and further factors, for example on the situation, whether other drugs are given in parallel.

The compounds can be administered orally and parenterally, Lp. (intraperitoneal), i. v.(intravenous),/./n.(intramuscular) or percutaneous. The compounds can also be implanted into the tissue. The amount administered can oscillate within a wide range, in which effective amount is applied. Depending on the condition being treated and the type of administration, the amount of a given compound can vary over a wide range. In humans, the daily dose is 0.1 to 10 mg.

The duration of application depends on the purpose to be achieved.

For application, capsules, pills, tablets, dragees, creams, ointments, lotions, liquids, such as syrups, gels, injectable liquids, for example for Lp.-, and. v-, Lm -or percutaneous injection, and so on, whereby certain forms of administration of the compounds according to the invention, according to their type, release into the body gradually or the entire amount in a short time.

For oral administration, capsules, pills, tablets, dragees and liquids or other known oral forms of administration are used as pharmaceutical preparations. In this case, the drugs can be formulated in such a way that the active substances are released either in a short time and are released into the body or have a depot effect, and a longer-lasting, light flow of the active substance into the body is also achieved. Dosing units can contain, in addition to 7a,17a-substituted 11 P-halogensteroids, one or more pharmaceutically acceptable carriers, for example substances to establish the rheology of the drug, surfactants, dissolution agents, microcapsules, microparticles, granules, further fillers, such as silicic acid, talc, sliding agents, colors, fragrances and other substances.

7a, 17a-substituted 11 p-halogensteroids according to the invention can also be specially formulated in the form of a solution, which is intended for oral use and which, in addition to the active 11 P-halogensteroid, also contains the following as components: a pharmaceutically acceptable oil and/or a pharmaceutically acceptable lipophilic, surface-active substance and/or a pharmaceutically acceptable hydrophilic, surface-active substance and/or a pharmaceutically acceptable, water-miscible solvent. For this further reference is made to WO-A-97/21440.

In order to achieve better bioavailability of steroids, compounds can also be formulated from cyclodextrin clathrate. For this purpose, compounds react with α-, β- or γ-cyclodextrins or their derivatives.

As far as creams, ointments, lotions and liquids that are applied externally are to be used, they must be composed in such a way that the compounds according to the invention are delivered to the body in sufficient quantity. These forms of administration contain auxiliary substances, for example, substances for establishing the rheology of the drug, surface-active substances, preservatives, dissolution agents, diluents, substances for increasing permeability for steroids according to the invention through the skin, dyes, fragrances and substances for protecting the skin as conditioners and moisture regulators. Along with the steroids according to the invention, other active substances can also be contained in the medicine.

For parenteral use, the active substances may be dissolved or suspended in a physiologically tolerable solvent. Oils with or without the addition of a solubilizing agent, a surfactant, a suspending or emulsifying agent are often used as dissolving agents. Examples of applied oils are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil. Any liquid carrier in which the compounds according to the invention are dissolved or emulsified can be used to formulate the preparation for injection. These liquids often contain substances for viscosity regulation, surfactants, preservatives, dissolution agents, diluents, and other additional substances, with which the solution is made isotonic. Along with 7a,17a-substituted 11p-halogensteroids, other active substances can also be administered. 11 P-halogensteroids according to the invention can be administered in the form of a depot injection or an implantable preparation, for example subcutaneously, which can be formulated in such a way as to allow a slow release of the active substance. For this, known techniques can be used, for example soluble or membrane-based depots. Implants can contain biodegradable polymers or synthetic silicones, for example silicone rubber, as inert substances. 11 p-Halogensteroids can further be incorporated into a patch for percutaneous administration.

The following examples serve for a more detailed explanation of the invention:

A. Microbiological synthesis: 1 la-Hydroxy-7a-methyl-estr-4-ene-3,17-dione (compound 4.B)

Example 1:

Erlenmeyer flask of 2 1 containing 1000 ml of nutrient solution, sterilized for 30 min in an autoclave at 121°C, of 3 wt. % glucose, 1 wt% corn-swell water, 0.2 wt% NaN03, 0.1 wt% KH2P04, 0.2 wt% K2HPO4, 0.05 wt% KC1, 0.05 wt% MgS04x 7H20, and 0.002 wt% FeS04x 7H20 (pH 6.0), seeded with hair culture. tubes of strain Gnomonia cingulata (CBS 15226) and shake for 72 h at 28°C on a rotary shaker with 165 revolutions per minute. A 20 L fermenter is seeded with this pre-plant, which is batched with 19 L of sterile medium of the same final composition as described for the pre-culture. In addition, before sterilization, 1.0 ml of silicone oil and 1.0 ml of svnperonic (oxalugintetraoxylate) were added as an antifoaming agent. After a growth phase of 12 hours at 0.7 bar overpressure, temperature 28°C, venting of 20 l/min and mixing speed of 250 rpm. a solution of 4.0 g of 17p-Hydroxy-7a-methylestr-4-en-3-one in 40 ml of DMF was added. Mixing and venting continued. After 135 hours, the culture broth was skimmed and extracted for 12 hours with 10 1 methylisobutylketone and 5 hours with 5 1 methylisobutylketone. The combined organic phases are evaporated to dryness. Silicone oil is washed with hexane. After chromatography on silica gel with a gradient of hexane and ethyl acetate, 1.64 g (39%) of 11a-Hydroxy-7a-methyl-ester-4-ene-3,17-dione was isolated.

Example 2:

Erlenmeyer flask of 2 1 containing 1000 ml of nutrient solution, sterilized for 30 min in an autoclave at 121 °C, of 3 wt. % glucose, 1 wt% corn swelling water, 0.2 wt% NaN03, 0.1 wt% KH2P04, 0.2 wt% K2HPO4, 0.05 wt% KC1, 0.05 wt% MgS04x 7H20, and 0.002 wt% FeSO, x 7H20 (pH 6.0), inoculated with a slant tube culture. strain Glomerella cingulata (IFO 15226) and shake for 72 h at 28°C on a rotary shaker with 165 revolutions per minute. A 20 L fermenter is seeded with this pre-culture, which is batched with 19 L of sterile medium of the same final composition as described for the pre-culture. In addition, before sterilization, 1.0 ml of silicone oil and 1.0 ml of detergent were added as a foaming agent. After a growth phase of 12 hours at 0.7 bar overpressure, temperature 28°C, venting of 10 l/min and mixing speed of 350 rpm. a solution of 2.0 g of 17B-Hydroxy-7a-methylestr-4-en-3-one in 30 ml of DMF was added. Mixing and venting continued. After 19 hours, the culture broth was skimmed and extracted for 16 hours with 20 1 methylisobutyl ketone and 23 hours with 20 1 methylisobutyl ketone. The combined organic phases are evaporated to dryness. The residue is mostly dissolved in methanol. The silicone oil is washed and filtered. It is evaporated and after chromatography on silica gel with a gradient of dichloromethane and acetone, 1.55 g (73%) of 1 la,17B-dihydroxy-7a-methylestr-4-en-3-one is isolated. After recrystallization from acetone/diisopropyl ether, 827 mg (39%) of white crystals of melting point 163°C and [a]d=-16° (CHCl3, c=0.501) were isolated.

Erlenmeyer flask of 2 1 containing 500 ml of nutrient solution, sterilized for 30 min in an autoclave at 121°C, of 0.5 wt. % glucose, 0.5 wt. of Bacto-yeast extract, 0.1% by weight of peptone, and 0.2% by weight of corn swelling water (pH 7.5), was inoculated with four cryo-spheres of Bacillus sphaericus (ATCC 7055) strain culture and shaken for 24 h at 28°C on a rotary shaker at 165 revolutions per minute. With this pre-culture, four 2 1 Erlenmeyer flasks containing 500 ml of sterile medium of the same composition as described for the pre-culture, each with 10% of this broth culture, are inoculated. After a growth phase of 4 hours at a temperature of 28°C, and a shaking speed of 165 rpm. on a rotary shaker, a solution of 50 mg of 11 a, 176-Dihydroxy-7a-methylestr-4-en-3-one in 2.5 ml of DMF was added to each Erlenmeyer flask. Shaking was continued for another 48 h. The combined broth cultures were extracted twice with 2 L each of methylisobutyl ketone. The combined organic phases are dried over sodium sulfate and evaporated to dryness. 630 mg of an oily-crystalline residue is obtained. After recrystallization from acetone/diisopropylether, 103 mg (42.9%) of yellowish crystals of melting point 189°C and [a]D=+40.4° (CHCl3, c=0.529) were isolated (direct crystallization without prior chromatographic purification).

Example 3:

Erlenmeyer of 2 1 containing 500 ml of nutrient solution, sterilized for 30 min in an autoclave at 121°C, of 3 wt. % glucose, 1 wt% corn-swelling water, 0.2 wt% NaN03, 0.1 wt% KH2P04, 0.2 wt% K2HPO4, 0.05 wt% KC1, 0.05 wt% MgS04x 7H20, and 0.002 wt% FeS04x 7H20 (pH 6.0), seeded with a half hair culture. tubes of the strain Aspergillus ochraceus (CBS 13252) and shake for 72 h at 28°C on a rotary shaker at 165 revolutions per minute. A 10 1 fermentor is seeded with this pre-plant, which is batched with 9.5 1 of sterile medium of the same final composition as described for the pre-culture. In addition, before sterilization, 0.5 ml of silicone oil and 0.5 ml of detergent were added as an antifoaming agent. After a growth phase of 6 hours at 0.7 bar overpressure, temperature 28°C, venting of 5 l/min and mixing speed of 350 rpm. a solution of 1.0 g of 7α-methylester-4-ene-3,17-dione in 15 ml of DMF was added. Mixing and venting continued. After 22 hours, the culture broth was skimmed and extracted twice for 4 hours with 7 1 of methylisobutyl ketone. The combined organic phases are evaporated to dryness. The residue is dissolved mainly in methanol. The silicone oil is filtered off. It was evaporated and after chromatography on silica gel with a gradient of dichloromethane and acetone, 0.78 g (74%) of 1 la-Hydroxy-7a-methyl-estr-4-ene-3,17-dione was isolated. After recrystallization from acetone/diisopropyl ether, 311 mg (29.6%) of white crystals melting at 200°C and [a]D=+52° were isolated.

(CHCl3, c=0.5905).

B. Chemical process of obtaining

Example 4: Preparation of li<p->Fluoro-17P-hydroxy-7a-methylestr-4-en-3one:

a) 11 P-Fluoro-7a-methylester-4-ene-3,17-dione

Into a solution of 13.08 g of 112-Hydroxy-7a-methylester-4-ene-3,17-dione

(obtained with the help of microbiological synthesis according to the invention [part A]) in 250 ml of toluene and 18.2 ml of 1,8-Diazabicyclo[5,4,0]undec-7-ene at 0°C, 11.5 ml of perfluorobutane-1-fluoride of sulfonic acid is added. After 1 h, it is neutralized with 2 M sodium acid, poured into water, extracted four times with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated in a vacuum. After chromatography of the crude product on silica gel with a gradient of hexane/ethyl acetate, 8.7 g of 11 P-Fluoro-7a-methylester-4-ene-3,17-dione of melting point 101.4°C [a]D:+135.8° (CHC13) is obtained.

b) 1 ip-Fluoro-17P-hydroxy-7a-methylestr-4-en-3-one:

A solution of 8.7 g of 1 ip -Fluoro-7a-methylester-4-ene-3,17-dione in 148 ml

of tetrahydrofuran was mixed dropwise at 0°C with 29.5 ml of IM lithium aluminum tri-tert-butoxyhydride in tetrahydrofuran and at 0°C for 5.5 h. Then dilute sulfuric acid is added at 0°C, and the reaction solution is poured onto ice water, extracted three times with ethyl acetate, washed

neutral, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/ethyl acetate. 5.8 g of 1 ip-Fluoro-17P-hydroxy-7a-methylestr-4-en-3-one of melting point 143-144°C [a]D= +89.9° (CHC13) is obtained.

Example 5: Preparation of 1 lp -Fluoro-17p-(4-sulfamoylbenzoxy)-7a-methylestr-4-en-3-one

A solution of 500 mg of 1 ip-Fluoro-17p-hydroxy-7a-methylestr-4-en-3-one in 7.5 ml of pyridine was mixed at room temperature with 750 mg of 4-sulfamoylbenzoic acid, 800 mg of N,N-dicyclohexylcarbodiimide as well as 125 mg of /7-toluenesulfonic acid and stirred for 8.5 h. Then it is poured onto sodium hydrogen carbonate solution, extracted four times with dichloromethane, washed neutral, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/acetone. 302 mg of 1 ip-Fluoro-17P-(4-sulfamoylbenzoxy)-7a-methylestr-4-en-3-one melting point 232°C are obtained. [α]D= +100.5° (CHCl 3 ).

Example 6: Preparation of 17a-Ethynyl-lip-fluoro-17P-hydroxy-7a-methylestr-4-en-3-one:

a) 1 ip-Fluoro-3-methoxy-7a-methylestra-3,5-dien-17-one:

A solution of 2 g of 1 ip-Fluoro-7a-methylester-4-ene-3,17-dione in 20 ml of 2,2-Di-methoxypropane was stirred for 6.5 h with 200 mg of pyridinium tosylate at 80°C. Then it is diluted with ethyl acetate, washed with a solution of sodium hydrogen carbonate and sodium chloride, dried over sodium sulfate and evaporated in a vacuum. 2 g of crude 1 ip -Fluoro-3-methoxy-7a-methylestra-3,5-dien-17-one are obtained.

b) 17a-Ethynyl-1 ip-fluoro-17p-hydroxy-7a-methylestr-4-en-3-one:

A solution of 9.17 g of Cer-III-chloride in 60 ml of tetrahydrofuranase at 0°C

mixed dropwise with 74.2 ml of ethynylmagnesium bromide solution (0.5 M in tetrahydrofuran) and stirred for 1 h at 0°C. Then a solution of 2 g of crude 1 ip -Fluoro-3-methoxy-7a-methylestra-3,5-dien-17-one in 40 ml of tetrahydrofuran was added dropwise and stirred for a further 3.5 h at 0°C. For the purpose of processing, a saturated solution of ammonium chloride is added, poured into water, extracted three times with ethyl acetate, washed with semi-concentrated sodium acid, solutions of sodium hydrogen carbonate, sodium chloride, evaporated in a vacuum and chromatographed in hexane/ethyl acetate. 1.15 g of pure 17a-Ethynyl-1 ip-fluoro-17P-hydroxy-7a-methylestr-4-en-3-one melting point 218-220°C are obtained. [a]D= +19.2°

(CHC13).

Example 7: Preparation of 17a-Ethynyl-1 ip-fluoro-17P-hydroxy-7a-methylestr-5(10)-en-3-one: a) 3,3-Ethandiyldioxy-17a-ethynyl-11 p-fluoro-7a-methylestr-5(10)-en-17p-ol Solution of 700 mg 17a-Ethynyl-l ip-fluoro-17P-hydroxy-7a-methylestr-4-en-3-one in 7 ml of dichloromethane and 4.7 ml of ethylene glycol is mixed for 6.5 h with 2.3 ml of triethyl orthoformate and 30 mg of p-toluenesulfonic acid hydrate at room temperature. Then it is poured onto sodium hydrogencarbonate solution, extracted several times with ethyl acetate, washed neutrally, dried over sodium sulfate, evaporated under vacuum and chromatographed on silica gel with hexane/ethyl acetate. 205 mg of 3,3-Ethanediyldioxy-17α-ethynyl-1β-fluoro-7α-methylestr-5(10)-en-17β-ol are obtained. b) 17a-Ethynyl-l ip-fluoro-17p-hydroxy-7a-methylestr-5(10)-en-3-one: A solution of 205 mg of 3,3-ethanediyldioxy-17a-ethynyl-l 1 p-fluoro-7a-methylestr-5(10)-en-17p-ol in 27 ml of methanol and 3.6 ml of water is mixed for 24 h with 361 mg of oxalic acid at room temperature. Then it is poured onto sodium hydrogencarbonate solution, extracted three times with ethyl acetate, washed neutrally, dried over sodium sulfate, evaporated in vacuo and chromatographed with hexane/ethyl acetate. 95 mg of 17a-Ethynyl-1 ip-fluoro-17P-hydroxy-7a-methylestr-5(10)-en-3-one melting point 112-114°C are obtained.

Example 8: Preparation of 17a-Ethynyl-li<p->fluoro-7a-methylestra-1,3,5(10)-trien-3,17P-diol: A solution of 500 mg of lip-fluoro-7a-methylestra-1,3,5(10)-trien-17-one in 16.5 ml of acetonitrile is mixed for 6.5 h with 400 mg of copper-II-bromide. 25°C. Then it is diluted with ethyl acetate, washed with a solution of sodium bicarbonate and sodium chloride, dried over sodium sulfate, evaporated under vacuum and chromatographed on silica gel with hexane/acetone. 280 mg of 17a-Ethynyl-1 ip-fluoro-7a-methylestra-1,3,5(10)-trien-3,17p-onata melting point 185-186°C are obtained. b) 17a-Ethynyl-11p-fluoro-7a-methylester-1,3,5(10)-triene-3,17P-diol: A suspension of 20.3 g of cerium-III-chloride in 7.5 ml of tetrahydrofuran is mixed dropwise at 0°C with 16.5 ml of ethynylmagnesium bromide solution (0.5 M in tetrahydrofuran) and stirred for 0.5 h. at 0°C. Then a solution of 280 mg of 1 lp-Fluor-3-hydroxy-7a-methylestra-1,3,5(10)-trien-17-one in 2.8 ml of tetrahydrofuran was added dropwise and stirred for a further 3.5 h at 0°C. For the purpose of processing, a saturated solution of ammonium chloride is added, poured onto water, extracted four times with ethyl acetate, washed neutrally, dried over sodium sulfate, evaporated in a vacuum and chromatographed with hexane/ethyl acetate. Get 220 mg

17a-Ethynyl-11P-fluoro-7a-methylester-1,3,5(10)-triene-3,17P-diol melting point 115-117°C.

Claims (5)

1. Microbiological procedure for obtaining 7a-substituted 11a-hydroxys steroids of the general formula 4,B indicated by what is R<7>grouping P-Q, whereby P represents Cr to C4-alkylene and Q is hydrogen, Cr to C4-alkyl or Cp to C4-fluoroalkyl and the group P-Q is linked via P to the steroid skeleton, R<10>is<z>a H, CH3 or CF3a R13 is methyl or ethyl, wherein the 7a-substituted steroids of the general formula D in which R<7>, R<10> and R<13>i<m> have the same meanings as stated above are hydroxylated using a microorganism selected from the group comprising Beauveria sp., Curvularia sp., Giberella sp., Glomerella sp., Gnomonia sp., Haplosporella sp., Helicostyllum sp., Nigrospora sp., and Syncephalastrum sp. 2. Microbiological procedure according to claim 1, indicated by the fact that the microorganism is selected from the group that includes Bauveria bassiana, Curvularia lunata, Gibberella zeae, Glomerella cingulata, Glomerella fusaroides, Gnomonia cingulata, Haplosporella hesperedica, Helicostylum piriformae, Nigrospora sphaericai Syncephalastrum racemosum. 3. Microbiological procedure according to one of claims 1 or 2, characterized in that R<7>st<o>is for CH3. 4. Microbiological procedure according to one of the requirements 1 to 3, indicated by the fact that R10 stands for H. 5. Microbiological process according to one of claims 1 to 4, indicated by the fact that R<13> stands for CH3.